Methyl tertiary-butyl ether (MTBE) is an oxygenated fuel additive added to gasoline to decrease carbon monoxide emissions during combustion. Both occupational and consumer exposure to MTBE are substantial due to its large production volume and widespread use. Among its hepatotoxic and nephrotoxic effects, it has also been shown to cause Leydig cell tumors (LCT) in both Sprague-Dawley and Fischer 344 male rats following chronic exposure (Belpoggi et al., 1995; Bird et al., 1997). This response coupled with its ability to cause a decrease in uterine weight and an increase in estrogen metabolism in female mice (Moser et al., 1998) suggests that MBTE may be disrupting normal hormonal signaling. It is therefore hypothesized that MTBE alters the clearance of steroids in rodents which causes changes in normal hypothalamus-pituitary- testicular (HPT) hormonal regulation. In this proposal we aim to 1) evaluate if MTBE is functioning as an endocrine-active compound in male Sprague-Dawley rats, 2) assess the ability of MTBE to alter the clearance of testosterone, and 3) assess the potential of MTBE to cause dynamic changes in the regulation of the endocrine system. An understanding of the ability of MTBE to alter the HPT axis will provide information necessary to study the mode of action by which this chemical causes LCT in male rats as well as to evaluate if this tumor response in humans would be of concern.